Effects of short-term experimental insulin resistance and family history of diabetes on pancreatic beta-cell function in nondiabetic individuals.

CONTEXT

Normal glucose homeostasis is maintained despite reductions in insulin sensitivity by increasing insulin secretion. This ability to compensate for reduced insulin sensitivity is highly heritable, but the mechanisms for this compensation or its failure in type 2 diabetes (T2DM) are unknown.

OBJECTIVE

The objective of this study was to test whether individuals with a family history of T2DM have a fixed decrease in beta-cell mass or function that would be revealed as an impaired insulin secretory response to short-term insulin resistance.

DESIGN

Glucose tolerance, insulin sensitivity (S(I)), and insulin response to i.v. glucose (AIR(G)) were compared in nondiabetic individuals with and without a family history of diabetes before and after nicotinic acid (NA) treatment.

SETTING

This study was performed at the Ambulatory General Clinical Research Center.

SUBJECTS

Healthy, nonobese, nondiabetic individuals with or without a family history of T2DM were studied.

INTERVENTIONS

Oral NA was given, with a final dose of 2 g/d, for at least 7 d.

MAIN OUTCOME MEASURE

The main outcome measure was the disposition index (insulin sensitivity x insulin response) in response to NA.

RESULTS

Postchallenge plasma glucose levels rose during NA therapy regardless of family history. Neither group adequately increased their AIR(G) to maintain the disposition index. Family members did not differ from controls at baseline or after NA treatment for any outcome measure, but only 28 of 52 subjects experienced a 25% or greater fall in S(I) with NA treatment.

CONCLUSIONS

Short-term beta-cell compensation to NA-induced insulin resistance was incomplete and did not differ by genetic predisposition. A genetic defect controlling beta-cell growth in response to chronic insulin resistance better explains differences in the ability to compensate for insulin resistance than an inherited, fixed defect in beta-cell mass.